Alcoholic liver cirrhosis (ALC) remains a major cause of morbidity and mortality and is the most common cause of liver disease In the developed world. It is unknown why only a minority of heavy and prolonged alcohol mis-users develop ALC. There is a weak relationship between the amount of alcohol consumed and development of ALC such that some develop severe liver disease with moderate levels of alcohol use although others with very high levels of consumption only progress to mild liver Injury. Apart from a greater vulnerability in women than men, few contributory factors have been identified for the development of ALC. To date, only one genetic polymorphism (in PNPLA3) has shown replicable positive result as a risk factor for ALC, although evidence from twin studies and Inter-ethnic variability in ALC mortality rates, supports a genetic component in ALC. Candidate gene studies have been inconclusive but these have generally been too small to yield definitive re-sults. Risk identification is likely to provide Insights into the pathogenic process and may suggest strategies for hami reduction. High-throughput genome-wide search for genetic changes called single nucleotide polymor-phlsms (SNPs) provides an ideal opportunity to Identify genes responsible for this polygenic disorder and is now technically feasible. We have gathered an experienced multidisciplinary team from the USA, Australia, France, Germany, Switzerland and UK with a proven track record in clinical alcoholic liver disease and in genetics. We propose to prospectively collect clinical data and DNA from 1250 heavy drinkers without known liver disease (Controls) and 1250 heavy drinkers with ALC (Cases). To these 2500 specimens we will add clinical data/DNAfrom more than 2700 heavy drinkers (~1100 with ALC) from existing databases/biorepositories in the possession of several study co-PIs. Cases and controls will be matched for age, gender, race/ethnicity and country of origin. DNA will be genotyped with the lllumina Human660-Quad SNP an-ay at CIDR to generate SNP profiles in the Cases and Controls. Data will be analysed to identify genetic variants that predispose some heavy drinkers to ALC in order to answer the question 'Why do only a minority of alcoholics develop liver cirrhosis?" PUBLIC HEALTH RELEVANCE: Identification of genetic risk factors that predispose some heavy drinkers to develop ALC will likely illuminate new biological pathways and generate new hypothesis on how alcohol damages the liver. This will lead to strategies to prevent liver disease and development of new treatment modalities.